Alzheimer disease (AD) is characterized by excessive deposition of the (3-amyloid peptide (QAP) in the central nervous system. Although several lines of evidence suggest that 3-AP is neurotoxic, a mechanism for (-AP toxicity in AD brain remains unclear. In this paper we provide both direct in vito evidence that S-AP can bind and activate the classical complement cytolytic pathway in the absence of antibody and indirect in situ evidence that such actions occur in the AD brain in association with areas of AD pathology.Alzheimer disease (AD) is characterized by excessive central nervous system (CNS) deposition of the f-amyloid peptide ((3-AP), a 40-to 42-amino acid peptide derived from a larger amyloid precursor protein (APP) (1-3). Although no specific mechanism of -3-AP deposition has yet been formally proven, there are several lines ofevidence (4-6) that, once generated, 3-AP causes direct or indirect toxicity to CNS neurons. Proposed mechanisms of AD neurotoxicity include membrane changes (7), alterations in Ca2+ homeostasis (6,8), excitotoxicity (5,6), and disruption of cytoskeletal or axon transport systems (9, 10). However, no single AD pathogenetic mechanism has yet achieved a wide consensus of acceptance.In addition to studies of 3-AP, over the last decade a number ofinvestigators have noted that the AD brain exhibits many of the classical markers of immune-mediated damage. These include elevated numbers of major histocompatibility complex class I-and II-immunoreactive microglia (cells believed to be an endogenous CNS form of the peripheral macrophage) (11-15) and astrocytes expressing interleukin 1 (16) and a1-antichymotrypsin (17) (both acute phase reactants). Of particular importance, complement proteins of the classical pathway have been immunohistochemically detected in the AD brain (12,13,(18)(19)(20), and we have noted that they most often appear associated with ,3-AP-containing pathological structures such as senile plaques. Proteins specific to the alternative pathway do not appear to be present (12,13,18). The first step in the classical complement pathway entails binding of the Clq component of C1, with subsequent activation of the Clr and Cls components. This is followed by a complex series of autocatalytic reactions, proceeding through C4, C2, and C3, and culminating in formation of the membrane attack complex (MAC), C5b-9. The MAC inserts a lytic plug in adjacent cell membranes, mediating cellular toxicity (21). Although Clq binding to the Fc region of immunoglobulins is the most common mechanism for initiating the classical pathway, several substratesincluding viruses, parasites, and mannan-binding proteinhave also been demonstrated to activate C1 and to do so in an antibody-independent fashion (22). In this paper we present six converging lines of evidence suggesting that S-AP activates the classical pathway complement cascade without mediation by immunoglobulin. This previously unrecognized mechanism may contribute significantly to the neurotoxicity of (3-AP as well as to the patho...

Large numbers of neuritic plaques (NP), largely composed of a fibrillar insoluble form of the β-amyloid peptide (Aβ), are found in the hippocampus and neocortex of Alzheimer's disease (AD) patients in association with damaged neuronal processes, increased numbers of activated astrocytes and microglia, and several proteins including the components of the proinflammatory complement system. These studies address the hypothesis that the activated complement system mediates the cellular changes that surround fibrillar Aβ deposits in NP. We report that Aβ peptides directly and independently activate the alternative complement pathway as well as the classical complement pathway; trigger the formation of covalent, ester-linked complexes of Aβ with activation products of the third complement component (C3); generate the cytokine-like C5a complement-activation fragment; and mediate formation of the proinflammatory C5b-9 membrane attack complex, in functionally active form able to insert into and permeabilize the membrane of neuronal precursor cells. These findings provide inflammation-based mechanisms to account for the presence of complement components in NP in association with damaged neurons and increased numbers of activated glial cells, and they have potential implications for the therapy of AD.

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